Field of the Invention
Compounds of this invention are analogues of natural prostaglandins.
Natural prostaglandins are twenty-carbon atom alicyclic compounds related to prostanoic acid which has the following structure: ##STR1## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereo-chemical feature of I is the trans-orientation of the side-chains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. All natural prostaglandins have this orientation. In I, as elsewhere in this specification, a dashed line (--) indicates projection of a covalent bond below the plane of a reference carbon atom (alpha-configuration), while a wedged line ( ) represents direction above that plane (beta-configuration). Those conventions apply to all compounds subsequently discussed in this specification.
In one system of nomenclature suggested by N. A. Nelson (J. Med. Chem., 17: 911 (1972), prostaglandins are named as derivatives or modifications of the natural prostaglandins. In a second system, the I.U.P.A.C. (International Union of Pure and Applied Chemistry) system of nomenclature, prostaglandins are named as substituted heptanoic acids. Yet a third system of nomenclature is frequently used by those skilled in the prostaglandin art. In this third system (also described by Nelson), all prostaglandins are named as derivatives or modifications of prostanoic acid (structure I) or prostane (the hydrocarbon equivalent of structure I). This system is used by Chemical Abstracts and may become an I.U.P.A.C. accepted system.
Natural prostaglandins have the structures, ##STR2## in which: L and M may be ethylene or cis-vinylene radicals and the five-membered ring ##STR3## may be: ##STR4##
Prostaglandins are classified according to the functional groups present in the five-membered ring and the presence of double bonds in the ring or chains. Prostaglandins of the A-class (PGA or prostaglandin A) are characterized by an oxo group at C.sub.9 and a double bond at C.sub.10 -C.sub.11 (.DELTA..sup.10,11); those of the B-class (PGB) have an oxo group at C.sub.9 and a double bond at C.sub.8 -C.sub.12 (.DELTA..sup.8,12); compounds of the C-class (PGC) contain an oxo group at C.sub.9 and a double bond at C.sub.11 -C.sub.12 (.DELTA..sup.11,12); members of the D-class (PGD) have an oxo group at C.sub.11 and an alpha-oriented hydroxy group at C.sub.9 ; prostaglandins of the E-class (PGE) have an oxo group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11 ; and members of the F-class (PGF) have an alpha-directed hydroxyl group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11. Within each of the A, B, C, D, E, and F classes of prostaglandins are three subclassifications based upon the presence of double bonds in the side-chains at C.sub.5 -C.sub.6, C.sub.13 -C.sub.14, or C.sub.17 -C.sub.18. The presence of a trans-unsaturated bond only at C.sub.13 -C.sub.14 is indicated by the subscript numeral 1; thus, for example, PGE.sub.1 (or prostaglandin E.sub.1) denotes a prostaglandin of the E-type (oxo group at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a trans-double bond at C.sub.13 -C.sub.14. The presence of both a trans-double bond at C.sub.13 -C.sub.14 and a cis-double bond at C.sub.5 -C.sub.6 is denoted by the subscript numeral 2; for example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13 -C.sub.14, a cis-double bond at C.sub.5 -C.sub.6 and a cis-double bond at C.sub.17 -C.sub.18 is indicated by the subscript numeral 3; for example, PGE.sub.3. The above notations apply to prostaglandins of the A, B, C, D, and F series as well, however, in the latter the alpha-orientation of the hydroxyl group at C.sub.9 is indicated by the subscript Greek letter .alpha. after the numerical subscript.
The three systems of nomenclature as they apply to natural PGF.sub.3.alpha. are shown below: ##STR5## Nelson System: Prostaglandin F.sub.3.alpha. or PGF.sub.3.alpha. (shortened form) I.U.P.A.C. System:
7-[3R, 5S-Dihydroxy-2R-(3S-hydroxy-1B,5Z-octadienyl)-cyclopent-1R-yl]-5Z-heptenoi c acid Third System (Chemical Abstracts): PA1 (5Z, 9.alpha., 11.alpha., 13E, 15S, 17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oic acid. PA1 D is a R-hydroxymethylene or S-hydroxymethylene radical; PA1 J is a methylene, R-hydroxymethylene, S-hydroxymethylene or a methine radical such that J is methine only when K is methine; PA1 K is a methylene, ethylene or a methine radical such that K is ethylene only when J is methylene and K is methine only when J is methine to form a carbon-carbon double covalent bond between J and K; PA1 L is a carbonyl, R-hydroxymethylene or S-hydroxymethylene radical; PA1 Q is an ethylene or Z-vinylene radical; PA1 T is an alkoxycarbonyl having from 1 to 3 carbon atoms inclusive in the alkyl chain, carboxyl, or hydroxymethyl radical or pharmacologically acceptable nontoxic carboxy salts; and PA1 B is a bicycloalkyl radical of the formula ##STR15## where m and p are integers having a value of from 1 to 4; n is an integer having a value of from 0 to 4 such that n is not 1 when m and p are both 2; and the sum of m, n and p is greater than or equal to 3 and where the point of attachment of the alkyl chain (CH.sub.2).sub.g to the bicycloalkyl radical is in the (CH.sub.2).sub.m bridge or bridgehead position. PA1 A is an acid-labile protecting group selected from the class consisting of 1-ethoxyethylene, trimethylsilyl, tert-butyl-dimethylsilyl, 2-ethoxy-prop-2-yl, triphenylmethyl, or tetrahydropyran-2-yl radicals; PA1 g is an integer having a value of from 0 to 10; and PA1 B is selected from the class of bicycloalkyl radicals of the formula: ##STR24## where m and p are integers having a value of from 1 to 4; n is an integer having a value of from 0 to 4 such that the sum of m, n and p is greater than or equal to 3 and the point of attachment of the alkyl chain (CH.sub.2).sub.g to the bicycloalkyl radical is in the (CH.sub.2).sub.m bridge or in the bridgehead position. PA1 Q is an ethylene or Z-vinylene radical; and PA1 J' is a R-hydroxymethylene radical protected with an acid-labile hydroxyl-protecting group A.
It is important to note that in all natural prostaglandins there is an alpha-oriented hydroxyl group at C.sub.15. In the Cahn-Ingold-Prelog system of defining stereochemistry, that C.sub.15 hydroxyl group is in the S-configuration. The Cahn-Ingold-Prelog system is used to define stereochemistry of any asymmetric center outside of the carbocyclic ring in all three systems of nomenclature described above. This is in contrast to some prostaglandin literature in which the .alpha.,.beta. designations are used, even at C.sub.15.
11-Deoxy derivatives of PGE and PGF molecules do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents 11-deoxy PGE and PGF compounds when: ##STR6## In this formula, and others of this patent specification a swung dash or serpentine line (.about.) denotes a covalent bond which can be either in the alpha configuration (projecting below the plane of a reference carbon atom) or in the beta configuration (projecting above the plane of a reference carbon atom).
PGF.sub..beta. molecules also do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents PGF.sub..beta. compounds when: ##STR7##
9-Deoxy derivatives of PGE do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents 9-deoxy PGE compounds when: ##STR8##
9-Deoxy-.DELTA..sup.9,10 derivatives of PGE do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represent 9-deoxy-.DELTA..sup.9,10 PGE compounds when: ##STR9##
9a-Homo- and 9a-homo-11-deoxy-derivative of PGE and PGF molecules do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents 9a-homo- and 9a-homo-11-deoxy-compounds of PGE and PGF when: ##STR10##
11a-Homo- derivatives of PGE, PGF and PGA molecules do not occur as such in nature, but constitute classes of compounds which are expected to posses biological activity related to the parent compounds. Formula II represents 11a-homo- derivatives of PGE, PGF and PGA molecules when: ##STR11##
11-Epi-PGE and PGF molecules do not occur as such in nature, but constitute classes of compounds which possess biological activity related to the parent compounds. Formula II represents 11-epi-compounds of PGE and PGF when: ##STR12##
8Iso-, 12iso or 8,12-bis iso (ent) prostaglandins do not occur as such in nature, but constitute classes of compounds which possess biological activity related to the parent compounds. Formula II represents 8iso-, 12iso- or 8,12-bis iso (ent) compounds when: ##STR13## These iso modifications of Formula II may be divided into all of the sub-classes with varying ring oxygenation as described above.
Recent research indicates that prostaglandins are ubiquitous in animal tissues and that prostaglandins, as well as their synthetic anlogues, have important biochemical and physiological effects in mammalian endocrine, reproductive, central and peripheral nervous, sensory, gastro-intestinal, hematic, respiratory, cardiovascular, and renal systems.
In mammalian endocrine systems, experimental evidence indicates prostaglandins are involved in the control of hormone synthesis or release in hormone-secretory glands. In rats, for example, PGE.sub.1 and PGE.sub.2 increase release of growth hormone while PGA.sub.1 increased synthesis of that hormone. In sheep, PGE.sub.1 and PGF.sub.1.alpha. inhibit ovarian progesterone secretion. In a variety of mammals, PGF.sub.1.alpha. and PGF.sub.2.alpha. act as luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha. and PGF.sub.1.beta. increase thyroid activity. In hypophysectomized rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.alpha. stimulate steroidogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens. In the female reproductive system, PGE and PGF.sub..alpha. compounds contract uterine smooth muscle. In general, PGE, PGB and PGA compounds relax in vitro human uterine muscle strips, while those of the PGF.sub..alpha. class contract such isolated preparations. PGE compounds in general promote fertility in the female reproductive system while PGF.sub.2.alpha. has contragestational effects. PGF.sub.2.alpha. also appears to be involved in the mechanism of menstruation. In general, PGE.sub.2 exerts potent oxytocic effects in inducing labor, while PGF.sub.2.alpha. induces spontaneous abortions in early pregnancy.
PGF.sub..alpha. and PGE compounds have been isolated from a variety of nervous tissue and they seem to act as neurotransmitters. PGE.sub.1 retards whereas PGF.sub.2.alpha. facilitates transmission in motor pathways in the central nervous system. It has been reported that PGE.sub.1 and PGE.sub.2 inhibit transmitter release from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1 and PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar activity in man.
In most mammalian respiratory tracts, compounds of the PGE and PGF class relax in vitro preparations of tracheal smooth muscle. In that preparation, PGE.sub.1 and PGE.sub.2 relax while PGF.sub.2.alpha. contracts the smooth muscle. PGE and PGF compounds are normally found in the human lung, and it is postulated that some cases of bronchial asthma involve an imbalance in the production or metabolism of those compounds.
Prostaglandins are involved in certain hematic mechanisms in mammals. PGE.sub.1, for example, inhibits thrombogenesis in vitro through its effects on blood platelets.
In a variety of mammalian cardiovascular systems, compounds of the PGE and PGA class are vasodilators whereas those of the PGF.sub..alpha. class are vasoconstrictors, by virtue of their action on vascular smooth muscle.
Prostaglandins are naturally found in the kidney and reverse experimental and clinical renoprival hypertension.
The clinical implications of prostaglandins and their analogues are far-ranging and include, but are not limited to the following: in obstetrics and gynecology, they may be useful in fertility control, treatment of menstrual disorders, induction of labor, and correction of hormone disorders; in gastroenterology, they may be useful in the treatment of peptic ulcers and various disorders involving motility, secretion, and absorption in the gastrointestinal tract; in the respiratory area, they may be beneficial in therapy of bronchial asthma and other diseases involving broncho-constriction; in hematology, they may have utility as anti-clotting agents in diseases such as venous thrombosis, thrombotic coronary occlusion and other diseases involving thrombi; in circulatory diseases they have therapeutic utility in hypertension, peripheral vasopathies, and cardiac disorders.
For a more complete review of chemical, physiological and pharmacological aspects of the prostaglandin, consult the following references: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180: 1-568(1971): and Higgins and Braunwald, J. Am. Med. Assn., 53: 92-112(1972).